Analyte sensors comprising leveling agents

ABSTRACT

Generally, embodiments of the invention relate to analyte determining methods and devices (e.g., electrochemical analyte monitoring systems) that have improved uniformity of distribution of one or more components of the sensor by inclusion of a low surface tension polymer leveling agent, where the components are disposed proximate to a working electrode of in vivo and/or in vitro analyte sensors, e.g., continuous and/or automatic in vivo monitoring using analyte sensors and/or test strips. Also provided are systems and methods of using the, for example electrochemical, analyte sensors in analyte monitoring.

BACKGROUND

In many instances it is desirable or necessary to regularly monitor theconcentration of particular constituents in a fluid. A number of systemsare available that analyze the constituents of bodily fluids such asblood, urine and saliva. Examples of such systems conveniently monitorthe level of particular medically significant fluid constituents, suchas, for example, cholesterol, ketones, vitamins, proteins, and variousmetabolites or blood sugars, such as glucose. Diagnosis and managementof patients suffering from diabetes mellitus, a disorder of the pancreaswhere insufficient production of insulin prevents normal regulation ofblood sugar levels, requires carefully monitoring of blood glucoselevels on a daily basis. A number of systems that allow individuals toeasily monitor their blood glucose are currently available. Such systemsinclude electrochemical biosensors, including those that comprise aglucose sensor that is adapted for insertion into a subcutaneous sitewithin the body for the continuous monitoring of glucose levels inbodily fluid of the subcutaneous site (see for example, U.S. Pat. No.6,175,752 to Say et al).

A person may obtain the blood sample by withdrawing blood from a bloodsource in his or her body, such as a vein, using a needle and syringe,for example, or by lancing a portion of his or her skin, using a lancingdevice, for example, to make blood available external to the skin, toobtain the necessary sample volume for in vitro testing. The person maythen apply the fresh blood sample to a test strip, whereupon suitabledetection methods, such as calorimetric, electrochemical, or photometricdetection methods, for example, may be used to determine the person'sactual blood glucose level. The foregoing procedure provides a bloodglucose concentration for a particular or discrete point in time, andthus, must be repeated periodically, in order to monitor blood glucoseover a longer period.

In addition to the discrete or periodic, in vitro, bloodglucose-monitoring systems described above, at least partiallyimplantable, or in vivo, blood glucose-monitoring systems, which areconstructed to provide continuous in vivo measurement of an individual'sblood glucose concentration, have been described and developed.

Such analyte monitoring devices are constructed to provide forcontinuous or automatic monitoring of analytes, such as glucose, in theblood stream or interstitial fluid. Such devices include electrochemicalsensors, at least a portion of which are operably positioned in a bloodvessel or in the subcutaneous tissue of a patient.

While continuous glucose monitoring is desirable, there are severalchallenges associated with optimizing manufacture protocols to improveyield and uniformity of the sensing layer and/or other layer (e.g., anoverlaying membrane) of the biosensors constructed for in vivo use.Accordingly, further development of manufacturing techniques andmethods, as well as analyte-monitoring devices, systems, or kitsemploying the same, is desirable.

SUMMARY OF THE INVENTION

Generally, embodiments of the invention relate to analyte determiningmethods and devices (e.g., electrochemical analyte monitoring systems)that have improved uniformity of distribution of one or more componentsof the sensor by inclusion of a low surface tension polymer levelingagent, where the components are disposed proximate to a workingelectrode of in vivo and/or in vitro analyte sensors, e.g., continuousand/or automatic in vivo monitoring using analyte sensors and/or teststrips. Also provided are systems and methods of using the, for exampleelectrochemical, analyte sensors in analyte monitoring.

These and other objects, advantages, and features of the invention willbecome apparent to those persons skilled in the art upon reading thedetails of the invention as more fully described below.

BRIEF DESCRIPTION OF THE DRAWINGS

A detailed description of various aspects, features and embodiments ofthe invention are provided herein with reference to the accompanyingdrawings, which are briefly described below. The drawings areillustrative and are not necessarily drawn to scale. The drawingsillustrate various aspects or features of the invention and mayillustrate one or more embodiment(s) or example(s) of the invention inwhole or in part. A reference numeral, letter, and/or symbol that isused in one drawing to refer to a particular element or feature maybeused in another drawing to refer to a like element or feature.

FIG. 1 shows a block diagram of an embodiment of a data monitoring andmanagement system according to embodiments of the invention.

FIG. 2 shows a block diagram of an embodiment of the transmitter unit ofthe data monitoring and management system of FIG. 1.

FIG. 3 shows a block diagram of an embodiment of the receiver/monitorunit of the data monitoring and management system of FIG. 1.

FIG. 4 shows a schematic diagram of an embodiment of an analyte sensoraccording to the embodiments of the invention.

FIGS. 5A-5B show a perspective view and a cross sectional view,respectively of another embodiment an analyte sensor.

FIG. 6A is a microphotograph of six deposition spots of a sensing layerformulation on a gold surface. The thick, dark outer ring encirclingeach spot represents the formation of the “coffee ring” effect referredto herein. FIG. 6B is a microphotograph of six deposition spots of asensing layer formulation on gold surface, wherein the sensing layerformulation comprises 2% of the low surface tension polymer levelingagent referred to as Dow Corning® 57 (DC 57). The microphotographillustrates the extent of homogeneity, and uniformity of solutiondistribution after curing that results when a low surface tensionpolymer leveling agent is added to the sensing layer formulation.

FIG. 7 is a microphotograph of three deposition spots of a sensing layerformulation on a gold surface, wherein the sensing layer formulationcomprises 2% of the low surface tension polymer leveling agent referredto as Dow Corning® 28 (DC 28). Again, the microphotograph illustratesthe extent of homogeneity, and uniformity of solution distribution thatresults when a low surface tension polymer leveling agent is added tothe sensing layer formulation.

FIG. 8 is a microphotograph of a single deposition spot of a sensinglayer formulation on a gold surface, wherein the sensing layerformulation comprises 2% of the low surface tension polymer levelingagent referred to as Surfynol® 2502. Again, the microphotographillustrates the extent of homogeneity, and uniformity of solutiondistribution that results when a low surface tension polymer levelingagent is added to the sensing layer formulation.

FIG. 9A, when juxtaposed against FIG. 9B, provides a comparison betweena control sensor in which the membrane formulation was not supplementedwith a low surface tension polymer leveling agent 10 days post cure at56° C. (FIG. 6A), versus a sensor with a membrane coating that wastreated with the low surface tension polymer dimethyl, methyl(polyethylene oxide acetate-capped) siloxane (“DC 57”) (FIG. 9B). After16 days at 56° C., the leveling agent-treated sensor membrane appearssmooth, homogenous and sturdy. FIG. 9B illustrates elimination ofwrinkling and a leveling of the “orange peel” effect.

FIG. 10 shows the results of sensitivity comparison (nA/mm²) at varyingconcentrations of glucose (mM) between control sensors (diamonds),sensors with the sensing layers supplemented with 1% of the low surfacetension polymer DC 57 (squares) and sensors with the sensing layerssupplemented with 3% of the low surface tension polymer DC 57(triangles).

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

Before the embodiments of the invention are described, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the embodiments of the invention will be limited only bythe appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimits of that range is also specifically disclosed. Each smaller rangebetween any stated value or intervening value in a stated range and anyother stated or intervening value in that stated range is encompassedwithin the invention. The upper and lower limits of these smaller rangesmay independently be included or excluded in the range, and each rangewhere either, neither or both limits are included in the smaller rangesis also encompassed within the invention, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the invention.

In the description of the invention herein, it will be understood that aword appearing in the singular encompasses its plural counterpart, and aword appearing in the plural encompasses its singular counterpart,unless implicitly or explicitly understood or stated otherwise. Merelyby way of example, reference to “an” or “the” “analyte” encompasses asingle analyte, as well as a combination and/or mixture of two or moredifferent analytes, reference to “a” or “the” “concentration value”encompasses a single concentration value, as well as two or moreconcentration values, and the like, unless implicitly or explicitlyunderstood or stated otherwise. Further, it will be understood that forany given component described herein, any of the possible candidates oralternatives listed for that component, may generally be usedindividually or in combination with one another, unless implicitly orexplicitly understood or stated otherwise. Additionally, it will beunderstood that any list of such candidates or alternatives, is merelyillustrative, not limiting, unless implicitly or explicitly understoodor stated otherwise.

Various terms are described below to facilitate an understanding of theinvention. It will be understood that a corresponding description ofthese various terms applies to corresponding linguistic or grammaticalvariations or forms of these various terms. It will also be understoodthat the invention is not limited to the terminology used herein, or thedescriptions thereof, for the description of particular embodiments.Merely by way of example, the invention is not limited to particularanalytes, bodily or tissue fluids, blood or capillary blood, or sensorconstructs or usages, unless implicitly or explicitly understood orstated otherwise, as such may vary.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the application. Nothing hereinis to be construed as an admission that the embodiments of the inventionare not entitled to antedate such publication by virtue of priorinvention. Further, the dates of publication provided may be differentfrom the actual publication dates which may need to be independentlyconfirmed.

Overview

Embodiments of the invention relate to methods and devices for improvingthe uniformity of distribution of one or more components of a sensor byinclusion of a low surface tension polymer leveling agent, where thecomponents are disposed proximate to a working electrode of the sensor,such as in vivo and/or in vitro analyte sensors, including, such as,continuous and/or automatic in vivo analyte sensors. For example,embodiments of the invention provide for inclusion of a low surfacetension polymer leveling agent in a solution, such as a sensing layerformulation and/or other layer (e.g., a membrane) formulation, resultingin reduction of the contact angle of the solution, thereby lowering thesolution surface tension. Also provided are systems and methods of usingthe analyte sensors in analyte monitoring.

In general, embodiments of the invention are based on the discovery thatthe addition of a low surface tension polymer to solution formulationsused in the manufacture of in vivo and/or in vitro biosensors greatlyimproves uniformity and/or distribution of one or more components of thesensor (e.g., an enzyme-containing sensing layer and/or one or moremembrane layer(s) of such devices). Low surface tension polymers areadditives that reduce the contact angle of the solution, therebylowering the solution surface tension. The contact angle is the angle atwhich a liquid or vapor interface meets a solid surface. The contactangle is specific for any given system. On many highly hydrophilicsurfaces, water droplets will exhibit contact angles of 0° to 30°. Ifthe solid surface is hydrophobic, the contact angle will be larger than90°. On highly hydrophobic surfaces, the surfaces have water contactangles as high as 150° or even nearly 180°. On these surfaces, waterdroplets simply rest on the surface, without actually wetting to anysignificant extent.

In general, the low surface tension polymers reduce the contact angle ofthe solution by migrating to the top of the solution and leveling thesurface. The result is a reduction and in some cases completeelimination of the “coffee ring” effect (see homogenous and uniformdistribution of each sample in FIG. 6B, FIG. 7 and FIG. 8). This resultsin a more uniform distribution of the constituents of a solutiondeposited on a substrate upon drying and curing, as well as a smoothersurface of the solution upon drying and curing as compared to a solutionlacking the low surface tension polymer. This, in turn, improves thecoefficient of variation and the overall manufacturing process of thesensor and overall system.

Suitable low surface tension polymers for use with the describedembodiments include, but are not limited to, polymeric compounds thatreduce the overall surface tension of the solution to which they areadded, thereby reducing the contact angle of the system between thesubstrate and the coating solution by about 3% to about 75%, includingabout 10% to about 50%, about 20% to about 40%, such as about 25% toabout 35%, and the like.

Examples of low surface tension polymer leveling agents suitable for usewith the subject methods, compositions and kits include, but are notlimited to, polyacrylates and polysiloxanes with modified chain ends,including polyether-modified polydimethylsiloxanes. Examples forillustration purposes may include surfactants, surface-tension modifiersand/or surface-tension reducers such as Polydimethylsiloxane(H₃C)₃Si[Si(CH₃)₂O]_(n)Si(CH₃)₃; Polyether modified Polydimethylsiloxane[CH₂O—]_(n)[Si(CH₃)₂O]_(n)—[CH₂O—]_(n); Poly((ethyleneoxide)(polyethylene oxide))butyl terminated PDMSCH₃—{[CH₂CH₂O]_(n)—[CH₂O—]_(n)}_(n)[Si(CH₃)₂O]_(n)—{[CH₂O—]_(n)[CH₂CH₂O]_(n)}_(n)—CH₃;and Dimethyl, methyl (polyethylene oxide acetate-capped) siloxane (DC57), wherein n is an integer in a range of from about 1 to 500. Anadditional example of a low surface tension polymer leveling agentsincludes Surfynol 2502 (Air Products and Chemicals, Inc., Allentown,Pa.; CAS Number: 182211-02-5), which may include alkoxylated acetylinicdiol ether or ethylenic diol modified with PEO (e.g., 5 moles) and PPO(e.g., 2 moles), oxirane, or1,4-dimethyl-1,4-bis(2-methylpropyl)-2-butyne-1,4-diyl ether.

The low surface tension polymer leveling agent may be included in anycomponent of a sensor that can benefit from improvement of adhesionand/or uniformity of distribution. Exemplary components include, but arenot limited to, formulations that provide reagents such as enzyme or thelike, such as a sensing layer having an analyte responsive enzyme, andone or more membrane layers that are used, inter alia, to promote one ormore functionality to the sensor, such as minimize interfering substanceand/or promote bio-compatibility and/or regulate-analyte (e.g., glucose)flux to in vivo biosensors for continuous glucose monitoring. Suchcomponents may be sensitive to the formation of crinkles and creasesupon curing, giving an “orange peel” effect, such that the surface ofthe layer may resemble an orange peel. In addition, the componentformulation of a sensor when contacted to the sensor (e.g., by dipcoating, spray coating, or the like) and cured may form a brittle shell.This phenomenon may give the device a brittleness that may cause it tocrack, break down and/or peel off of the substrate. Thesecharacteristics may cause the membrane to slough, chip and peel offcarbon and other substrates. In some instances, this chipping can resultin the undesirable deposition of residual pieces of the membrane invivo. In addition, the components of a solution are also sensitive tomigrating and settling along the outer perimeter of the deposition,referred to as formation of a “coffee ring” effect on the substrate.

Additional exemplary components of a sensor that may be suitablyformulated with a low surface tension polymer leveling agent aredescribed in U.S. Pat. Nos. 5,262,035, 5,262,305, 6,134,461, 6,143,164,6,175,752, 6,338,790, 6,579,690, 6,654,625, 6,736,957, 6,746,582,6,932,894, 6,605,200, 6,605,201, 7,090,756, 6,746,582 as well as thosedescribed in U.S. patent application Ser. Nos. 11/701,138, 11/948,915,all of which are incorporated herein by reference in their entirety.

In some embodiments, the low surface tension polymer leveling agent isformulated with a sensing layer that is disposed proximate to theworking electrode. Generally, an embodiment of a sensing layer may bedescribed as the area shown schematically in FIG. 5B as 508. The sensinglayer may be described as the active chemical area of the biosensor. Thesensing layer formulation, which can include a glucose-transducingagent, may include, for example, among other constituents, a redoxmediator, such as, for example, a hydrogen peroxide or a transitionmetal complex, such as a ruthenium-containing complex or anosmium-containing complex, and an analyte response enzyme, such as, forexample, a glucose responsive enzyme (e.g., glucose oxidase, glucosedehydrogenase, etc.) or lactate responsive enzyme (e.g., lactateoxidase). The sensing layer may also include other optional components,such as, for example, a polymer and a bi-functional, short-chain,epoxide cross-linker, such as PEG.

Any suitable proportion of low surface tension polymer may be used witha sensing layer, where the specifics will depend on, e.g., theparticular sensing layer, etc. In certain embodiments, the low surfacetension polymer leveling agents may comprise from about 0.5% to about60% by weight of the total biosensor sensing layer formulation. Forexample, such low surface tension polymer leveling agents may comprisefrom about 1% to about 30% by weight of the total biosensor sensinglayer formulation, including, for example, about 5% to about 25%, about8% to about 22%, about 10% to about 20%, about 12% to about 18%, about14% to about 16%, and the like.

In other embodiments, in addition to or instead of being employed with asensing layer, a low surface tension polymer leveling agent may beformulated with one or more other layers of a sensor, e.g., a membranethat is disposed over at least a portion of the sensing layer of theworking electrode. Any suitable proportion of low surface tensionpolymer may be used with such one or more layers, where the specificswill depend on, e.g., the particular layer, etc. In certain embodiments,the low surface tension polymer leveling agent may comprise from about0.001% to about 10% by weight of the total biosensor membraneformulation. For example, such low surface tension polymer levelingagents may comprise from about 0.001% to about 1% by weight of the totalbiosensor membrane formulation, including, for example, about 0.01% toabout 0.9%, about 0.05% to about 0.5%, about 0.08% to about 0.2%, about0.09% to about 0.1%, and the like.

In an electrochemical embodiment, the sensor is placed,transcutaneously, for example, into a subcutaneous site such thatsubcutaneous fluid of the site comes into contact with the sensor. Inother in vivo embodiments, placement of at least a portion of the sensormay be in a blood vessel. The sensor operates to electrolyze an analyteof interest in the subcutaneous fluid such that a current is generatedbetween the working electrode and the counter electrode. A value for thecurrent associated with the working electrode is determined. If multipleworking electrodes are used, current values from each of the workingelectrodes may be determined. A microprocessor may be used to collectthese periodically determined current values or to further process thesevalues.

If an analyte concentration is successfully determined, it may bedisplayed, stored, and/or otherwise processed to provide usefulinformation. By way of example, raw signal or analyte concentrations maybe used as a basis for determining a rate of change in analyteconcentration, which should not change at a rate greater than apredetermined threshold amount. If the rate of change of analyteconcentration exceeds the predefined threshold, an indication maybedisplayed or otherwise transmitted to indicate this fact.

As demonstrated herein, the methods of the invention are particularlyuseful in connection with a device that is used to measure or monitor aglucose analyte, such as any such device described herein. These methodsmay also be used in connection with a device that is used to measure ormonitor another analyte, including oxygen, carbon dioxide, proteins,drugs, or another moiety of interest, for example, or any combinationthereof, found in bodily fluid, including subcutaneous fluid, dermalfluid (sweat, tears, and the like), interstitial fluid, or other bodilyfluid of interest, for example, or any combination thereof. In general,the device is in good contact, such as thorough and substantiallycontinuous contact, with the bodily fluid.

According to an embodiment of the invention, the measurement sensor isone suited for electrochemical measurement of analyte concentration,such as, for example, glucose concentration, in a bodily fluid. In thisembodiment, the measurement sensor comprises at least a workingelectrode and a counter electrode. Another embodiment may furthercomprise a reference electrode. The working electrode is typicallyassociated with a glucose-responsive enzyme. A mediator may also beincluded. In certain embodiments, hydrogen peroxide, which may becharacterized as a mediator, is produced by a reaction of the sensor andmay be used to infer the concentration of glucose. In some embodiments,a mediator is added to the sensor by a manufacturer, i.e., is includedwith the sensor even prior to use. Generally, a redox mediator isrelative to the working electrode and is capable of transferringelectrons between a compound and a working electrode, either directly orindirectly. Merely by way of example, the redox mediator may be, and is,for example, immobilized on the working electrode, e.g., entrapped on asurface or chemically bound to a surface.

Electrochemical Sensors

Embodiments of the invention relate to methods and devices for detectingat least one analyte, including glucose, in body fluid. Embodimentsrelate to the continuous and/or automatic in vivo monitoring of thelevel of one or more analytes using a continuous analyte monitoringsystem that includes an analyte sensor at least a portion of which is tobe positioned beneath a skin surface of a user for a period of timeand/or the discrete monitoring of one or more analytes using an in vitroblood glucose (“BG”) meter and an analyte test strip. Embodimentsinclude combined or combinable devices, systems and methods and/ortransferring data between an in vivo continuous system and an in vivosystem. In some embodiments, the systems, or at least a portion of thesystems, are integrated into a single unit.

A sensor that includes a low surface tension polymer may be an in vivosensor or an in vitro sensor (i.e., a discrete monitoring test strip).Such a sensor can be formed on a substrate, e.g., a substantially planarsubstrate. In certain embodiments, such a sensor is a wire, e.g., aworking electrode wire inner portion with one or more other electrodesassociated (e.g., on, including wrapped around) therewith. The sensormay also include at least one counter electrode (or counter/referenceelectrode) and/or at least one reference electrode or at least onereference/counter electrode.

Accordingly, embodiments include analyte monitoring devices and systemsthat include an analyte sensor at least a portion of which ispositionable beneath the skin of the user for the in vivo detection, ofan analyte, including glucose, lactate, and the like, in a body fluid.Embodiments include wholly implantable analyte sensors and analytesensors in which only a portion of the sensor is positioned under theskin and a portion of the sensor resides above the skin, e.g., forcontact to a sensor control unit (which may include a transmitter), areceiver/display unit, transceiver, processor, etc. The sensor may be,for example, subcutaneously positionable in a patient for the continuousor periodic monitoring of a level of an analyte in a patient'sinterstitial fluid. For the purposes of this description, continuousmonitoring and periodic monitoring will be used interchangeably, unlessnoted otherwise. The sensor response may be correlated and/or convertedto analyte levels in blood or other fluids. In certain embodiments, ananalyte sensor may be positioned in contact with interstitial fluid todetect the level of glucose, which detected glucose may be used to inferthe glucose level in the patient's bloodstream. Analyte sensors may beinsertable into a vein, artery, or other portion of the body containingfluid. Embodiments of the analyte sensors of the subject inventionhaving a low surface tension polymer may be configured for monitoringthe level of the analyte over a time period which may range fromseconds, minutes, hours, days, weeks, to months, or longer.

Of interest are analyte sensors, such as glucose sensors, having a lowsurface tension polymer, that are capable of in vivo detection of ananalyte for about one hour or more, e.g., about a few hours or more,e.g., about a few days or more, e.g., about three or more days, e.g.,about five days or more, e.g., about seven days or more, e.g., aboutseveral weeks or at least one month or more. Future analyte levels maybe predicted based on information obtained, e.g., the current analytelevel at time t₀, the rate of change of the analyte, etc. Predictivealarms may notify the user of a predicted analyte levels that may be ofconcern in advance of the user's analyte level reaching the futurelevel. This provides the user an opportunity to take corrective action.

FIG. 1 shows a data monitoring and management system such as, forexample, an analyte (e.g., glucose) monitoring system 100 in accordancewith certain embodiments. Embodiments of the subject invention arefurther described primarily with respect to glucose monitoring devicesand systems, and methods of glucose detection, for convenience only andsuch description is in no way intended to limit the scope of theinvention. It is to be understood that the analyte monitoring system maybe configured to monitor a variety of analytes at the same time or atdifferent times.

Analytes that may be monitored include, but are not limited to, acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin,creatine kinase (e.g., CK-MB), creatine, creatinine, DNA, fructosamine,glucose, glutamine, growth hormones, hormones, ketone bodies, lactate,peroxide, prostate-specific antigen, prothrombin, RNA, thyroidstimulating hormone, and troponin. The concentration of drugs, such as,for example, antibiotics (e.g., gentamicin, vancomycin, and the like),digitoxin, digoxin, drugs of abuse, theophylline, and warfarin, may alsobe monitored. In those embodiments that monitor more than one analyte,the analytes may be monitored at the same or different times.

The analyte monitoring system 100 includes a sensor 101, a dataprocessing unit 102 connectable to the sensor 101, and a primaryreceiver unit 104 which is configured to communicate with the dataprocessing unit 102 via a communication link 103. In certainembodiments, the primary receiver unit 104 may be further configured totransmit data to a data processing terminal 105 to evaluate or otherwiseprocess or format data received by the primary receiver unit 104. Thedata processing terminal 105 may be configured to receive data directlyfrom the data processing unit 102 via a communication link which mayoptionally be configured for bi-directional communication. Further, thedata processing unit 102 may include a transmitter or a transceiver totransmit and/or receive data to and/or from the primary receiver unit104 and/or the data processing terminal 105 and/or optionally thesecondary receiver unit 106.

Also shown in FIG. 1 is an optional secondary receiver unit 106 which isoperatively coupled to the communication link and configured to receivedata transmitted from the data processing unit 102. The secondaryreceiver unit 106 may be configured to communicate with the primaryreceiver unit 104, as well as the data processing terminal 105. Thesecondary receiver unit 106 may be configured for bi-directionalwireless communication with each of the primary receiver unit 104 andthe data processing terminal 105. As discussed in further detail below,in certain embodiments the secondary receiver unit 106 may be ade-featured receiver as compared to the primary receiver, i.e., thesecondary receiver may include a limited or minimal number of functionsand features as compared with the primary receiver unit 104. As such,the secondary receiver unit 106 may include a smaller (in one or more,including all, dimensions), compact housing or embodied in a deviceincluding a wrist watch, arm band, PDA, etc., for example.Alternatively, the secondary receiver unit 106 may be configured withthe same or substantially similar functions and features as the primaryreceiver unit 104. The secondary receiver unit 106 may include a dockingportion to be mated with a docking cradle unit for placement by, e.g.,the bedside for night time monitoring, and/or a bi-directionalcommunication device. A docking cradle may recharge a powers supply.

Only one sensor 101, data processing unit 102 and data processingterminal 105 are shown in the embodiment of the analyte monitoringsystem 100 illustrated in FIG. 1. However, it will be appreciated by oneof ordinary skill in the art that the analyte monitoring system 100 mayinclude more than one sensor 101 and/or more than one data processingunit 102, and/or more than one data processing terminal 105. Multiplesensors may be positioned in a patient for analyte monitoring at thesame or different times. In certain embodiments, analyte informationobtained by a first positioned sensor may be employed as a comparison toanalyte information obtained by a second sensor. This may be useful toconfirm or validate analyte information obtained from one or both of thesensors. Such redundancy may be useful if analyte information iscontemplated in critical therapy-related decisions. In certainembodiments, a first sensor may be used to calibrate a second sensor.

The analyte monitoring system 100 may be a continuous monitoring system,or semi-continuous, or a discrete monitoring system. In amulti-component environment, each component may be configured to beuniquely identified by one or more of the other components in the systemso that communication conflict may be readily resolved between thevarious components within the analyte monitoring system 100. Forexample, unique IDs, communication channels, and the like, may be used.

In certain embodiments, the sensor 101 is physically positioned in or onthe body of a user whose analyte level is being monitored. The sensor101 may be configured to at least periodically sample the analyte levelof the user and convert the sampled analyte level into a correspondingsignal for transmission by the data processing unit 102. The dataprocessing unit 102 is coupleable to the sensor 101 so that both devicesare positioned in or on the user's body, with at least a portion of theanalyte sensor 101 positioned transcutaneously. The data processing unitmay include a fixation element such as adhesive or the like to secure itto the user's body. A mount (not shown) attachable to the user andmateable with the unit 102 may be used. For example, a mount may includean adhesive surface. The data processing unit 102 performs dataprocessing functions, where such functions may include but are notlimited to, filtering and encoding of data signals, each of whichcorresponds to a sampled analyte level of the user, for transmission tothe primary receiver unit 104 via the communication link 103. In oneembodiment, the sensor 101 or the data processing unit 102 or a combinedsensor/data processing unit may be wholly implantable under the skinlayer of the user.

In certain embodiments, the primary receiver unit 104 may include ananalog interface section including and RF receiver and an antenna thatis configured to communicate with the data processing unit 102 via thecommunication link 103, and a data processing section for processing thereceived data from the data processing unit 102 including data decoding,error detection and correction, data clock generation, data bitrecovery, etc., or any combination thereof.

In operation, the primary receiver unit 104 in certain embodiments isconfigured to synchronize with the data processing unit 102 to uniquelyidentify the data processing unit 102, based on, for example, anidentification information of the data processing unit 102, andthereafter, to periodically receive signals transmitted from the dataprocessing unit 102 associated with the monitored analyte levelsdetected by the sensor 101.

Referring again to FIG. 1, the data processing terminal 105 may includea personal computer, a portable computer including a laptop or ahandheld device (e.g., personal digital assistants (PDAs), telephoneincluding a cellular phone (e.g., a multimedia and Internet-enabledmobile phone including an iPhone™, iPOD™ or similar phone), mp3 player,pager, and the like), drug delivery device, each of which may beconfigured for data communication with the receiver via a wired or awireless connection. Additionally, the data processing terminal 105 mayfurther be connected to a data network (not shown) for storing,retrieving, updating, and/or analyzing data corresponding to thedetected analyte level of the user.

The data processing terminal 105 may include an infusion device such asan insulin infusion pump or the like, which may be configured toadminister insulin to patients, and which may be configured tocommunicate with the primary receiver unit 104 for receiving, amongothers, the measured analyte level. Alternatively, the primary receiverunit 104 may be configured to integrate an infusion device therein sothat the primary receiver unit 104 is configured to administer insulin(or other appropriate drug) therapy to patients, for example, foradministering and modifying basal profiles, as well as for determiningappropriate boluses for administration based on, among others, thedetected analyte levels received from the data processing unit 102. Aninfusion device may be an external device or an internal device (whollyimplantable in a user).

In certain embodiments, the data processing terminal 105, which mayinclude an insulin pump, may be configured to receive the analytesignals from the data processing unit 102, and thus, incorporate thefunctions of the primary receiver unit 104 including data processing formanaging the patient's insulin therapy and analyte monitoring. Incertain embodiments, the communication link 103 as well as one or moreof the other communication interfaces shown in FIG. 1, may use one ormore of: an RF communication protocol, an infrared communicationprotocol, a Bluetooth enabled communication protocol, an 802.11xwireless communication protocol, or an equivalent wireless communicationprotocol which would allow secure, wireless communication of severalunits (for example, per HIPPA requirements), while avoiding potentialdata collision and interference.

FIG. 2 shows a block diagram of an embodiment of a data processing unitof the data monitoring and detection system shown in FIG. 1. User inputand/or interface components may be included or a data processing unitmay be free of user input and/or interface components. In certainembodiments, one or more application-specific integrated circuits (ASIC)may be used to implement one or more functions or routins associatedwith the operations of the data processing unit (and/or receiver unit)using for example one or more state machines and buffers.

As can be seen in the embodiment of FIG. 2, the sensor unit 101 (FIG. 1)includes four contacts, three of which are electrodes—work electrode (W)210, reference electrode (R) 212, and counter electrode (C) 213, eachoperatively coupled to the analog interface 201 of the data processingunit 102. This embodiment also shows optional guard contact (G) 211.Fewer or greater electrodes may be employed. For example, the counterand reference electrode functions may be served by a singlecounter/reference electrode, there may be more than one workingelectrode and/or reference electrode and/or counter electrode, etc.

FIG. 3 is a block diagram of an embodiment of a receiver/monitor unitsuch as the primary receiver unit 104 of the data monitoring andmanagement system shown in FIG. 1. The primary receiver unit 104includes one or more of: a blood glucose test strip interface 301, an RFreceiver 302, an input 303, a temperature detection section 304, and aclock 305, each of which is operatively coupled to a processing andstorage section 307. The primary receiver unit 104 also includes a powersupply 306 operatively coupled to a power conversion and monitoringsection 308. Further, the power conversion and monitoring section 308 isalso coupled to the receiver processor 307. Moreover, also shown are areceiver serial communication section 309, and an output 310, eachoperatively coupled to the processing and storage unit 307. The receivermay include user input and/or interface components or may be free ofuser input and/or interface components.

In certain embodiments, the test strip interface 301 includes a glucoselevel testing portion to receive a blood (or other body fluid sample)glucose test or information related thereto. For example, the interfacemay include a test strip port to receive a glucose test strip. Thedevice may determine the glucose level of the test strip, and optionallydisplay (or otherwise notice) the glucose level on the output 310 of theprimary receiver unit 104. Any suitable test strip may be employed,e.g., test strips that only require a very small amount (e.g., onemicroliter or less, e.g., 0.5 microliter or less, e.g., 0.1 microliteror less), of applied sample to the strip in order to obtain accurateglucose information, e.g. FreeStyle® blood glucose test strips fromAbbott Diabetes Care, Inc. Glucose information obtained by the in vitroglucose testing device may be used for a variety of purposes,computations, etc. For example, the information may be used to calibratesensor 101, confirm results of the sensor 101 to increase the confidencethereof (e.g., in instances in which information obtained by sensor 101is employed in therapy related decisions), etc.

In further embodiments, the data processing unit 102 and/or the primaryreceiver unit 104 and/or the secondary receiver unit 105, and/or thedata processing terminal/infusion section 105 may be configured toreceive the blood glucose value wirelessly over a communication linkfrom, for example, a blood glucose meter. In further embodiments, a usermanipulating or using the analyte monitoring system 100 (FIG. 1) maymanually input the blood glucose value using, for example, a userinterface (for example, a keyboard, keypad, voice commands, and thelike) incorporated in the one or more of the data processing unit 102,the primary receiver unit 104, secondary receiver unit 105, or the dataprocessing terminal/infusion section 105.

Additional detailed descriptions are provided in U.S. Pat. Nos.5,262,035; 5,264,104; 5,262,305; 5,320,715; 5,593,852; 6,175,752;6,650,471; 6,746,582, and in application Ser. No. 10/745,878 filed Dec.26, 2003 entitled “Continuous Glucose Monitoring System and Methods ofUse”, each of which is incorporated herein by reference.

FIG. 4 schematically shows an embodiment of an analyte sensor inaccordance with the embodiments of the invention. This sensor embodimentincludes electrodes 401, 402 and 403 on a base 404. Electrodes (and/orother features) may be applied or otherwise processed using any suitabletechnology, e.g., chemical vapor deposition (CVD), physical vapordeposition, sputtering, reactive sputtering, printing, coating, ablating(e.g., laser ablation), painting, dip coating, etching, and the like.Materials include, but are not limited to, any one or more of aluminum,carbon (including graphite), cobalt, copper, gallium, gold, indium,iridium, iron, lead, magnesium, mercury (as an amalgam), nickel,niobium, osmium, palladium, platinum, rhenium, rhodium, selenium,silicon (e.g., doped polycrystalline silicon), silver, tantalum, tin,titanium, tungsten, uranium, vanadium, zinc, zirconium, mixturesthereof, and alloys, oxides, or metallic compounds of these elements.

The sensor may be wholly implantable in a user or may be configured sothat only a portion is positioned within (internal) a user and anotherportion outside (external) a user. For example, the sensor 400 mayinclude a portion positionable above a surface of the skin 410, and aportion positioned below the skin. In such embodiments, the externalportion may include contacts (connected to respective electrodes of thesecond portion by traces) to connect to another device also external tothe user such as a transmitter unit. While the embodiment of FIG. 4shows three electrodes side-by-side on the same surface of base 404,other configurations are contemplated, e.g., fewer or greaterelectrodes, some or all electrodes on different surfaces of the base orpresent on another base, some or all electrodes stacked together,electrodes of differing materials and dimensions, etc.

FIG. 5A shows a perspective view of an embodiment of an electrochemicalanalyte sensor 500 having a first portion (which in this embodiment maybe characterized as a major portion) positionable above a surface of theskin 510, and a second portion (which in this embodiment may becharacterized as a minor portion) that includes an insertion tip 530positionable below the skin, e.g., penetrating through the skin andinto, e.g., the subcutaneous space 520, in contact with the user'sbiofluid such as interstitial fluid. Contact portions of a workingelectrode 501, a reference electrode 502, and a counter electrode 503are positioned on the portion of the sensor 500 situated above the skinsurface 510. Working electrode 501, a reference electrode 502, and acounter electrode 503 are shown at the second section and particularlyat the insertion tip 530. Traces may be provided from the electrode atthe tip to the contact, as shown in FIG. 5A. It is to be understood thatgreater or fewer electrodes may be provided on a sensor. For example, asensor may include more than one working electrode and/or the counterand reference electrodes may be a single counter/reference electrode,etc.

FIG. 5B shows a cross sectional view of a portion of the sensor 500 ofFIG. 5A. The electrodes 501, 502 and 503, of the sensor 500 as well asthe substrate and the dielectric layers are provided in a layeredconfiguration or construction. For example, as shown in FIG. 5B, in oneaspect, the sensor 500 (such as the sensor unit 101 FIG. 1), includes asubstrate layer 504, and a first conducting layer 501 such as carbon,gold, etc., disposed on at least a portion of the substrate layer 504,and which may provide the working electrode. Also shown disposed on atleast a portion of the first conducting layer 501 is a sensing layer508.

A first insulation layer such as a first dielectric layer 505 isdisposed or layered on at least a portion of the first conducting layer501, and further, a second conducting layer 509 may be disposed orstacked on top of at least a portion of the first insulation layer (ordielectric layer) 505. As shown in FIG. 5B, the second conducting layer509 may provide the reference electrode 502, as described herein havingan extended lifetime, which includes a layer of redox polymer asdescribed herein.

A second insulation layer 506 such as a dielectric layer in oneembodiment may be disposed or layered on at least a portion of thesecond conducting layer 509. Further, a third conducting layer 503 mayprovide the counter electrode 503. It may be disposed on at least aportion of the second insulation layer 506. Finally, a third insulationlayer may be disposed or layered on at least a portion of the thirdconducting layer 503. In this manner, the sensor 500 may be layered suchthat at least a portion of each of the conducting layers is separated bya respective insulation layer (for example, a dielectric layer). Theembodiment of FIGS. 5A and 5B show the layers having different lengths.Some or all of the layers may have the same or different lengths and/orwidths.

In certain embodiments, some or all of the electrodes 501, 502, 503 maybe provided on the same side of the substrate 504 in the layeredconstruction as described above, or alternatively, may be provided in aco-planar manner such that two or more electrodes may be positioned onthe same plane (e.g., side-by side (e.g., parallel) or angled relativeto each other) on the substrate 504. For example, co-planar electrodesmay include a suitable spacing there between and/or include dielectricmaterial or insulation material disposed between the conductinglayers/electrodes. Furthermore, in certain embodiments one or more ofthe electrodes 501, 502, 503 may be disposed on opposing sides of thesubstrate 504. In such embodiments, contact pads may be one the same ordifferent sides of the substrate. For example, an electrode may be on afirst side and its respective contact may be on a second side, e.g., atrace connecting the electrode and the contact may traverse through thesubstrate.

As noted above, analyte sensors may include an analyte-responsive enzymeto provide a sensing component or sensing layer. Some analytes, such asoxygen, can be directly electrooxidized or electroreduced on a sensor,and more specifically at least on a working electrode of a sensor. Otheranalytes, such as glucose and lactate, require the presence of at leastone electron transfer agent and/or at least one catalyst to facilitatethe electrooxidation or electroreduction of the analyte. Catalysts mayalso be used for those analytes, such as oxygen, that can be directlyelectrooxidized or electroreduced on the working electrode. For theseanalytes, each working electrode includes a sensing layer (see forexample sensing layer 408 of FIG. 5B) proximate to or on a surface of aworking electrode. In many embodiments, a sensing layer is formed nearor on only a small portion of at least a working electrode.

The sensing layer includes one or more components constructed tofacilitate the electrochemical oxidation or reduction of the analyte.The sensing layer may include, for example, a catalyst to catalyze areaction of the analyte and produce a response at the working electrode,an electron transfer agent to transfer electrons between the analyte andthe working electrode (or other component), or both.

A variety of different sensing layer configurations may be used. Incertain embodiments, the sensing layer is deposited on the conductivematerial of a working electrode. The sensing layer may extend beyond theconductive material of the working electrode. In some cases, the sensinglayer may also extend over other electrodes, e.g., over the counterelectrode and/or reference electrode (or counter/reference is provided).

A sensing layer that is in direct contact with the working electrode maycontain an electron transfer agent to transfer electrons directly orindirectly between the analyte and the working electrode, and/or acatalyst to facilitate a reaction of the analyte. For example, aglucose, lactate, or oxygen electrode may be formed having a sensinglayer which contains a catalyst, including glucose oxidase, glucosedehydrogenase, lactate oxidase, or laccase, respectively, and anelectron transfer agent that facilitates the electrooxidation of theglucose, lactate, or oxygen, respectively.

In other embodiments the sensing layer is not deposited directly on theworking electrode. Instead, the sensing layer 64 may be spaced apartfrom the working electrode, and separated from the working electrode,e.g., by a separation layer. A separation layer may include one or moremembranes or films or a physical distance. In addition to separating theworking electrode from the sensing layer the separation layer may alsoact as a mass transport limiting layer and/or an interferent eliminatinglayer and/or a biocompatible layer.

In certain embodiments which include more than one working electrode,one or more of the working electrodes may not have a correspondingsensing layer, or may have a sensing layer which does not contain one ormore components (e.g., an electron transfer agent and/or catalyst)needed to electrolyze the analyte. Thus, the signal at this workingelectrode may correspond to background signal which may be removed fromthe analyte signal obtained from one or more other working electrodesthat are associated with fully-functional sensing layers by, forexample, subtracting the signal.

In certain embodiments, the sensing layer includes one or more electrontransfer agents. Electron transfer agents that may be employed areelectroreducible and electrooxidizable ions or molecules having redoxpotentials that are a few hundred millivolts above or below the redoxpotential of the standard calomel electrode (SCE). The electron transferagent may be organic, organometallic, or inorganic. Examples of organicredox species are quinones and species that in their oxidized state havequinoid structures, such as Nile blue and indophenol. Examples oforganometallic redox species are metallocenes including ferrocene.Examples of inorganic redox species are hexacyanoferrate (III),ruthenium hexamine etc. Additional examples include those described inU.S. Pat. No. 6,736,957 and U.S. Patent Publication Nos. 2004/00796532006/0201805, the disclosures of which are incorporated herein byreference in their entirety.

In certain embodiments, electron transfer agents have structures orcharges which prevent or substantially reduce the diffusional loss ofthe electron transfer agent during the period of time that the sample isbeing analyzed. For example, electron transfer agents include but arenot limited to a redox species, e.g., bound to a polymer which can inturn be disposed on or near the working electrode. The bond between theredox species and the polymer may be covalent, coordinative, or ionic.Although any organic, organometallic or inorganic redox species may bebound to a polymer and used as an electron transfer agent, in certainembodiments the redox species is a transition metal compound or complex,e.g., osmium, ruthenium, iron, and cobalt compounds or complexes. Itwill be recognized that many redox species described for use with apolymeric component may also be used, without a polymeric component.

One type of polymeric electron transfer agent contains a redox speciescovalently bound in a polymeric composition. An example of this type ofmediator is poly(vinylferrocene). Another type of electron transferagent contains an ionically-bound redox species. This type of mediatormay include a charged polymer coupled to an oppositely charged redoxspecies. Examples of this type of mediator include a negatively chargedpolymer coupled to a positively charged redox species such as an osmiumor ruthenium polypyridyl cation. Another example of an ionically-boundmediator is a positively charged polymer including quaternizedpoly(4-vinyl pyridine) or poly(l-vinyl imidazole) coupled to anegatively charged redox species such as ferricyanide or ferrocyanide.In other embodiments, electron transfer agents include a redox speciescoordinatively bound to a polymer. For example, the mediator may beformed by coordination of an osmium or cobalt 2,2′-bipyridyl complex topoly(l-vinyl imidazole) or poly(4-vinyl pyridine).

Suitable electron transfer agents are osmium transition metal complexeswith one or more ligands, each ligand having a nitrogen-containingheterocycle such as 2,2′-bipyridine, 1,10-phenanthroline, 1-methyl,2-pyridyl biimidazole, or derivatives thereof. The electron transferagents may also have one or more ligands covalently bound in a polymer,each ligand having at least one nitrogen-containing heterocycle, such aspyridine, imidazole, or derivatives thereof. One example of an electrontransfer agent includes (a) a polymer or copolymer having pyridine orimidazole functional groups and (b) osmium cations complexed with twoligands, each ligand containing 2,2′-bipyridine, 1,10-phenanthroline, orderivatives thereof, the two ligands not necessarily being the same.Some derivatives of 2,2′-bipyridine for complexation with the osmiumcation include but are not limited to 4,4′-dimethyl-2,2′-bipyridine andmono-, di-, and polyalkoxy-2,2′-bipyridines, including4,4′-dimethoxy-2,2′-bipyridine. Derivatives of 1,10-phenanthroline forcomplexation with the osmium cation include but are not limited to4,7-dimethyl-1,10-phenanthroline and mono, di-, andpolyalkoxy-1,10-phenanthrolines, such as4,7-dimethoxy-1,10-phenanthroline. Polymers for complexation with theosmium cation include but are not limited to polymers and copolymers ofpoly(l-vinyl imidazole) (referred to as “PVI”) and poly(4-vinylpyridine) (referred to as “PVP”). Suitable copolymer substituents ofpoly(1-vinyl imidazole) include acrylonitrile, acrylamide, andsubstituted or quaternized N-vinyl imidazole, e.g., electron transferagents with osmium complexed to a polymer or copolymer of poly(l-vinylimidazole).

Embodiments may employ electron transfer agents having a redox potentialranging from about −200 mV to about +200 mV versus the standard calomelelectrode (SCE). The sensing layer may also include a catalyst which iscapable of catalyzing a reaction of the analyte. The catalyst may also,in some embodiments, act as an electron transfer agent. One example of asuitable catalyst is an enzyme which catalyzes a reaction of theanalyte. For example, a catalyst, including a glucose oxidase, glucosedehydrogenase (e.g., pyrroloquinoline quinone (PQQ), dependent glucosedehydrogenase, flavine adenine dinucleotide (FAD) dependent glucosedehydrogenase, or nicotinamide adenine dinucleotide (NAD) dependentglucose dehydrogenase), may be used when the analyte of interest isglucose. A lactate oxidase or lactate dehydrogenase may be used when theanalyte of interest is lactate. Laccase may be used when the analyte ofinterest is oxygen or when oxygen is generated or consumed in responseto a reaction of the analyte.

The sensing layer may also include a catalyst which is capable ofcatalyzing a reaction of the analyte. The catalyst may also, in someembodiments, act as an electron transfer agent. One example of asuitable catalyst is an enzyme which catalyzes a reaction of theanalyte. For example, a catalyst, including a glucose oxidase, glucosedehydrogenase (e.g., pyrroloquinoline quinone (PQQ), dependent glucosedehydrogenase or oligosaccharide dehydrogenase, flavine adeninedinucleotide (FAD) dependent glucose dehydrogenase, nicotinamide adeninedinucleotide (NAD) dependent glucose dehydrogenase), may be used whenthe analyte of interest is glucose. A lactate oxidase or lactatedehydrogenase may be used when the analyte of interest is lactate.Laccase may be used when the analyte of interest is oxygen or whenoxygen is generated or consumed in response to a reaction of theanalyte.

In certain embodiments, a catalyst may be attached to a polymer, crosslinking the catalyst with another electron transfer agent, which, asdescribed above, may be polymeric. A second catalyst may also be used incertain embodiments. This second catalyst may be used to catalyze areaction of a product compound resulting from the catalyzed reaction ofthe analyte. The second catalyst may operate with an electron transferagent to electrolyze the product compound to generate a signal at theworking electrode. Alternatively, a second catalyst may be provided inan interferent-eliminating layer to catalyze reactions that removeinterferents.

In certain embodiments, the sensor includes the low surface tensionpolymer and works at a gentle oxidizing potential, e.g., a potential ofabout +40 mV vs. Ag/AgCl. This sensing layer uses, for example, anosmium (Os)-based mediator constructed for low potential operation andincludes a low surface tension polymer. Accordingly, in certainembodiments the sensing element is a redox active component thatincludes (1) Osmium-based mediator molecules that include (bidente)ligands, and (2) glucose oxidase enzyme molecules. These twoconstituents are combined together with a low surface tension polymer.

A mass transport limiting layer (not shown), e.g., an analyte fluxmodulating layer, may be included with the sensor to act as adiffusion-limiting barrier to reduce the rate of mass transport of theanalyte, for example, glucose or lactate, into the region around theworking electrodes. The mass transport limiting layers are useful inlimiting the flux of an analyte to a working electrode in anelectrochemical sensor so that the sensor is linearly responsive over alarge range of analyte concentrations and is easily calibrated. Masstransport limiting layers may include polymers and may be biocompatible.A mass transport limiting layer may provide many functions, e.g.,biocompatibility and/or interferent-eliminating, etc.

In certain embodiments, a mass transport limiting layer is a membranecomposed of crosslinked polymers containing heterocyclic nitrogengroups, such as polymers of polyvinylpyridine and polyvinylimidazole. Insome embodiments, the low surface tension polymer is combined with themass transport limiting layer or membrane. Embodiments also includemembranes that are made of a polyurethane, or polyether urethane, orchemically related material, or membranes that are made of silicone, andthe like.

A membrane may be formed by crosslinking in situ a polymer, modifiedwith a zwitterionic moiety, a non-pyridine copolymer component, andoptionally another moiety that is either hydrophilic or hydrophobic,and/or has other desirable properties, in an alcohol-buffer solution. Incertain embodiments, the membrane formulation further includes a lowsurface tension polymer. The modified polymer may be made from aprecursor polymer containing heterocyclic nitrogen groups. For example,a precursor polymer may be polyvinylpyridine or polyvinylimidazole.Optionally, hydrophilic or hydrophobic modifiers may be used to“fine-tune” the permeability of the resulting membrane to an analyte ofinterest. Optional hydrophilic modifiers, such as poly(ethylene glycol),hydroxyl or polyhydroxyl modifiers, may be used to enhance thebiocompatibility of the polymer or the resulting membrane.

A membrane may be formed in situ by applying an alcohol-buffer solutionof a crosslinker and a modified polymer over an enzyme-containingsensing layer and allowing the solution to cure for about one to twodays or other appropriate time period. The crosslinker-polymer solutionmay be applied to the sensing layer by placing a droplet or droplets ofthe solution on the sensor, by dipping the sensor into the solution, orthe like. Generally, the thickness of the membrane is controlled by theconcentration of the solution, by the number of droplets of the solutionapplied, by the number of times the sensor is dipped in the solution, orby any combination of these factors. A membrane applied in this mannermay have any combination of the following functions: (1) mass transportlimitation, i.e., reduction of the flux of analyte that can reach thesensing layer, (2) biocompatibility enhancement, or (3) interferentreduction.

In certain embodiments, the sensing system detects hydrogen peroxide toinfer glucose levels. For example, a hydrogen peroxide-detecting sensormay be constructed in which a sensing layer includes enzyme such asglucose oxides, glucose dehydrogenase, or the like, and is positionedproximate to the working electrode. The sensing layer may be covered byone or more layers, e.g., a membrane that is selectively permeable toglucose. Once the glucose passes through the membrane, it is oxidized bythe enzyme and reduced glucose oxidase can then be oxidized by reactingwith molecular oxygen to produce hydrogen peroxide.

Certain embodiments include a hydrogen peroxide-detecting sensorconstructed from a sensing layer prepared by combining together, forexample: (1) a redox mediator having a transition metal complexincluding an Os polypyridyl complexes with oxidation potentials of about+200 mV vs. SCE, (2) a low surface tension polymer, and (3) periodateoxidized horseradish peroxidase (HRP). Such a sensor functions in areductive mode; the working electrode is controlled at a potentialnegative to that of the Os complex, resulting in mediated reduction ofhydrogen peroxide through the HRP catalyst.

In another example, a potentiometric sensor can be constructed asfollows. A glucose-sensing layer is constructed by combining together(1) a redox mediator having a transition metal complex including an Ospolypyridyl complexes with oxidation potentials from about −200 mV to+200 mV vs. SCE, and (2) a low surface tension polymer, and (3) glucoseoxidase. This sensor can then be used in a potentiometric mode, byexposing the sensor to a glucose containing solution, under conditionsof zero current flow, and allowing the ratio of reduced/oxidized Os toreach an equilibrium value. The reduced/oxidized Os ratio varies in areproducible way with the glucose concentration, and will cause theelectrode's potential to vary in a similar way.

The substrate may be formed using a variety of non-conducting materials,including, for example, polymeric or plastic materials and ceramicmaterials. Suitable materials for a particular sensor may be determined,at least in part, based on the desired use of the sensor and propertiesof the materials.

In some embodiments, the substrate is flexible. For example, if thesensor is configured for implantation into a patient, then the sensormay be made flexible (although rigid sensors may also be used forimplantable sensors) to reduce pain to the patient and damage to thetissue caused by the implantation of and/or the wearing of the sensor. Aflexible substrate often increases the patient's comfort and allows awider range of activities. Suitable materials for a flexible substrateinclude, for example, non-conducting plastic or polymeric materials andother non-conducting, flexible, deformable materials. Examples of usefulplastic or polymeric materials include thermoplastics such aspolycarbonates, polyesters (e.g., Mylar™ and polyethylene terephthalate(PET)), polyvinyl chloride (PVC), polyurethanes, polyethers, polyamides,polyimides, or copolymers of these thermoplastics, such as PETG(glycol-modified polyethylene terephthalate).

In other embodiments, the sensors are made using a relatively rigidsubstrate to, for example, provide structural support against bending orbreaking. Examples of rigid materials that may be used as the substrateinclude poorly conducting ceramics, such as aluminum oxide and silicondioxide. One advantage of an implantable sensor having a rigid substrateis that the sensor may have a sharp point and/or a sharp edge to aid inimplantation of a sensor without an additional insertion device.

It will be appreciated that for many sensors and sensor applications,both rigid and flexible sensors will operate adequately. The flexibilityof the sensor may also be controlled and varied along a continuum bychanging, for example, the composition and/or thickness of thesubstrate.

In addition to considerations regarding flexibility, it is oftendesirable that implantable sensors should have a substrate which isphysiologically harmless, for example, a substrate approved by aregulatory agency or private institution for in vivo use.

The sensor may include optional features to facilitate insertion of animplantable sensor. For example, the sensor may be pointed at the tip toease insertion. In addition, the sensor may include a barb which assistsin anchoring the sensor within the tissue of the patient duringoperation of the sensor. However, the barb is typically small enough sothat little damage is caused to the subcutaneous tissue when the sensoris removed for replacement.

An implantable sensor may also, optionally, have an anticlotting agentdisposed on a portion of the substrate which is implanted into apatient. This anticlotting agent may reduce or eliminate the clotting ofblood or other body fluid around the sensor, particularly afterinsertion of the sensor. Blood clots may foul the sensor orirreproducibly reduce the amount of analyte which diffuses into thesensor. Examples of useful anticlotting agents include heparin andtissue plasminogen activator (TPA), as well as other known anticlottingagents.

The anticlotting agent may be applied to at least a portion of that partof the sensor that is to be implanted. The anticlotting agent may beapplied, for example, by bath, spraying, brushing, or dipping. Theanticlotting agent is allowed to dry on the sensor. The anticlottingagent may be immobilized on the surface of the sensor or it may beallowed to diffuse away from the sensor surface. Typically, thequantities of anticlotting agent disposed on the sensor are far belowthe amounts typically used for treatment of medical conditions involvingblood clots and, therefore, have only a limited, localized effect.

Insertion Device

An insertion device can be used to subcutaneously insert the sensor intothe patient. The insertion device is typically formed using structurallyrigid materials, such as metal or rigid plastic. Exemplary materialsinclude stainless steel and ABS (acrylonitrile-butadiene-styrene)plastic. In some embodiments, the insertion device is pointed and/orsharp at the tip to facilitate penetration of the skin of the patient. Asharp, thin insertion device may reduce pain felt by the patient uponinsertion of the sensor. In other embodiments, the tip of the insertiondevice has other shapes, including a blunt or flat shape. Theseembodiments may be particularly useful when the insertion device doesnot penetrate the skin but rather serves as a structural support for thesensor as the sensor is pushed into the skin.

Sensor Control Unit

The sensor control unit can be integrated in the sensor, part or all ofwhich is subcutaneously implanted or it can be configured to be placedon the skin of a patient. The sensor control unit is optionally formedin a shape that is comfortable to the patient and which may permitconcealment, for example, under a patient's clothing. The thigh, leg,upper arm, shoulder, or abdomen are convenient parts of the patient'sbody for placement of the sensor control unit to maintain concealment.However, the sensor control unit may be positioned on other portions ofthe patient's body. One embodiment of the sensor control unit has athin, oval shape to enhance concealment. However, other shapes and sizesmay be used.

The particular profile, as well as the height, width, length, weight,and volume of the sensor control unit may vary and depends, at least inpart, on the components and associated functions included in the sensorcontrol unit. In general, the sensor control unit includes a housingtypically formed as a single integral unit that rests on the skin of thepatient. The housing typically contains most or all of the electroniccomponents of the sensor control unit.

The housing of the sensor control unit may be formed using a variety ofmaterials, including, for example, plastic and polymeric materials,particularly rigid thermoplastics and engineering thermoplastics.Suitable materials include, for example, polyvinyl chloride,polyethylene, polypropylene, polystyrene, ABS polymers, and copolymersthereof. The housing of the sensor control unit may be formed using avariety of techniques including, for example, injection molding,compression molding, casting, and other molding methods. Hollow orrecessed regions may be formed in the housing of the sensor controlunit. The electronic components of the sensor control unit and/or otheritems, including a battery or a speaker for an audible alarm, may beplaced in the hollow or recessed areas.

The sensor control unit is typically attached to the skin of thepatient, for example, by adhering the sensor control unit directly tothe skin of the patient with an adhesive provided on at least a portionof the housing of the sensor control unit which contacts the skin or bysuturing the sensor control unit to the skin through suture openings inthe sensor control unit.

When positioned on the skin of a patient, the sensor and the electroniccomponents within the sensor control unit are coupled via conductivecontacts. The one or more working electrodes, counter electrode (orcounter/reference electrode), optional reference electrode, and optionaltemperature probe are attached to individual conductive contacts. Forexample, the conductive contacts are provided on the interior of thesensor control unit. Other embodiments of the sensor control unit havethe conductive contacts disposed on the exterior of the housing. Theplacement of the conductive contacts is such that they are in contactwith the contact pads on the sensor when the sensor is properlypositioned within the sensor control unit.

Sensor Control Unit Electronics

The sensor control unit also typically includes at least a portion ofthe electronic components that operate the sensor and the analytemonitoring device system. The electronic components of the sensorcontrol unit typically include a power supply for operating the sensorcontrol unit and the sensor, a sensor circuit for obtaining signals fromand operating the sensor, a measurement circuit that converts sensorsignals to a desired format, and a processing circuit that, at minimum,obtains signals from the sensor circuit and/or measurement circuit andprovides the signals to an optional transmitter. In some embodiments,the processing circuit may also partially or completely evaluate thesignals from the sensor and convey the resulting data to the optionaltransmitter and/or activate an optional alarm system if the analytelevel exceeds a threshold. The processing circuit often includes digitallogic circuitry.

The sensor control unit may optionally contain a transmitter fortransmitting the sensor signals or processed data from the processingcircuit to a receiver/display unit; a data storage unit for temporarilyor permanently storing data from the processing circuit; a temperatureprobe circuit for receiving signals from and operating a temperatureprobe; a reference voltage generator for providing a reference voltagefor comparison with sensor-generated signals; and/or a watchdog circuitthat monitors the operation of the electronic components in the sensorcontrol unit.

Moreover, the sensor control unit may also include digital and/or analogcomponents utilizing semiconductor devices, including transistors. Tooperate these semiconductor devices, the sensor control unit may includeother components including, for example, a bias control generator tocorrectly bias analog and digital semiconductor devices, an oscillatorto provide a clock signal, and a digital logic and timing component toprovide timing signals and logic operations for the digital componentsof the circuit.

As an example of the operation of these components, the sensor circuitand the optional temperature probe circuit provide raw signals from thesensor to the measurement circuit. The measurement circuit converts theraw signals to a desired format, using for example, a current-to-voltageconverter, current-to-frequency converter, and/or a binary counter orother indicator that produces a signal proportional to the absolutevalue of the raw signal. This may be used, for example, to convert theraw signal to a format that can be used by digital logic circuits. Theprocessing circuit may then, optionally, evaluate the data and providecommands to operate the electronics.

Calibration

Sensors may be configured to require no system calibration or no usercalibration. For example, a sensor may be factory calibrated and neednot require further calibrating. In certain embodiments, calibration maybe required, but may be done without user intervention, i.e., may beautomatic. In those embodiments in which calibration by the user isrequired, the calibration may be according to a predetermined scheduleor may be dynamic, i.e., the time for which may be determined by thesystem on a real-time basis according to various factors, including, butnot limited to, glucose concentration and/or temperature and/or rate ofchange of glucose, etc.

In addition to a transmitter, an optional receiver may be included inthe sensor control unit. In some cases, the transmitter is atransceiver, operating as both a transmitter and a receiver. Thereceiver may be used to receive calibration data for the sensor. Thecalibration data may be used by the processing circuit to correctsignals from the sensor. This calibration data may be transmitted by thereceiver/display unit or from some other source such as a control unitin a doctor's office. In addition, the optional receiver may be used toreceive a signal from the receiver/display units to direct thetransmitter, for example, to change frequencies or frequency bands, toactivate or deactivate the optional alarm system and/or to direct thetransmitter to transmit at a higher rate.

Calibration data may be obtained in a variety of ways. For instance, thecalibration data may simply be factory-determined calibrationmeasurements which can be input into the sensor control unit using thereceiver or may alternatively be stored in a calibration data storageunit within the sensor control unit itself (in which case a receiver maynot be needed). The calibration data storage unit may be, for example, areadable or readable/writeable memory circuit.

Calibration may be accomplished using an in vitro test strip (or otherreference), e.g., a small sample test strip such as a test strip thatrequires less than about 1 microliter of sample (for example FreeStyle®blood glucose monitoring test strips from Abbott Diabetes Care). Forexample, test strips that require less than about 1 nanoliter of samplemay be used. In certain embodiments, a sensor may be calibrated usingonly one sample of body fluid per calibration event. For example, a userneed only lance a body part one time to obtain sample for a calibrationevent (e.g., for a test strip), or may lance more than one time within ashort period of time if an insufficient volume of sample is firstlyobtained. Embodiments include obtaining and using multiple samples ofbody fluid for a given calibration event, where glucose values of eachsample are substantially similar. Data obtained from a given calibrationevent may be used independently to calibrate or combined with dataobtained from previous calibration events, e.g., averaged includingweighted averaged, etc., to calibrate. In certain embodiments, a systemneed only be calibrated once by a user, where recalibration of thesystem is not required.

Alternative or additional calibration data may be provided based ontests performed by a doctor or some other professional or by thepatient. For example, it is common for diabetic individuals to determinetheir own blood glucose concentration using commercially availabletesting kits. The results of this test is input into the sensor controlunit either directly, if an appropriate input device (e.g., a keypad, anoptical signal receiver, or a port for connection to a keypad orcomputer) is incorporated in the sensor control unit, or indirectly byinputting the calibration data into the receiver/display unit andtransmitting the calibration data to the sensor control unit.

Other methods of independently determining analyte levels may also beused to obtain calibration data. This type of calibration data maysupplant or supplement factory-determined calibration values.

In some embodiments of the invention, calibration data may be requiredat periodic intervals, for example, every eight hours, once a day, oronce a week, to confirm that accurate analyte levels are being reported.Calibration may also be required each time a new sensor is implanted orif the sensor exceeds a threshold minimum or maximum value or if therate of change in the sensor signal exceeds a threshold value. In somecases, it may be necessary to wait a period of time after theimplantation of the sensor before calibrating to allow the sensor toachieve equilibrium. In some embodiments, the sensor is calibrated onlyafter it has been inserted. In other embodiments, no calibration of thesensor is needed.

Analyte Monitoring Device

In some embodiments of the invention, the analyte monitoring deviceincludes a sensor control unit and a sensor. In these embodiments, theprocessing circuit of the sensor control unit is able to determine alevel of the analyte and activate an alarm system if the analyte levelexceeds a threshold. The sensor control unit, in these embodiments, hasan alarm system and may also include a display, such as an LCD or LEDdisplay.

A threshold value is exceeded if the datapoint has a value that isbeyond the threshold value in a direction indicating a particularcondition. For example, a datapoint which correlates to a glucose levelof 200 mg/dL exceeds a threshold value for hyperglycemia of 180 mg/dL,because the datapoint indicates that the patient has entered ahyperglycemic state. As another example, a datapoint which correlates toa glucose level of 65 mg/dL exceeds a threshold value for hypoglycemiaof 70 mg/dL because the datapoint indicates that the patient ishypoglycemic as defined by the threshold value. However, a datapointwhich correlates to a glucose level of 75 mg/dL would not exceed thesame threshold value for hypoglycemia because the datapoint does notindicate that particular condition as defined by the chosen thresholdvalue.

An alarm may also be activated if the sensor readings indicate a valuethat is beyond a measurement range of the sensor. For glucose, thephysiologically relevant measurement range is typically about 30 to 400mg/dL, including about 40-300 mg/dL and about 50-250 mg/dL, of glucosein the interstitial fluid.

The alarm system may also, or alternatively, be activated when the rateof change or acceleration of the rate of change in analyte levelincrease or decrease reaches or exceeds a threshold rate oracceleration. For example, in the case of a subcutaneous glucosemonitor, the alarm system might be activated if the rate of change inglucose concentration exceeds a threshold value which might indicatethat a hyperglycemic or hypoglycemic condition is likely to occur.

A system may also include system alarms that notify a user of systeminformation such as battery condition, calibration, sensor dislodgment,sensor malfunction, etc. Alarms may be, for example, auditory and/orvisual. Other sensory-stimulating alarm systems may be used includingalarm systems which heat, cool, vibrate, or produce a mild electricalshock when activated.

Drug Delivery System

The subject invention also includes sensors used in sensor-based drugdelivery systems. The system may provide a drug to counteract the highor low level of the analyte in response to the signals from one or moresensors. Alternatively, the system may monitor the drug concentration toensure that the drug remains within a desired therapeutic range. Thedrug delivery system may include one or more (e.g., two or more)sensors, a processing unit such as a transmitter, a receiver/displayunit, and a drug administration system. In some cases, some or allcomponents may be integrated in a single unit. A sensor-based drugdelivery system may use data from the one or more sensors to providenecessary input for a control algorithm/mechanism to adjust theadministration of drugs, e.g., automatically or semi-automatically. Asan example, a glucose sensor may be used to control and adjust theadministration of insulin from an external or implanted insulin pump.

Each of the various references, presentations, publications, provisionaland/or non-provisional U.S. patent applications, U.S. patents, non-U.S.patent applications, and/or non-U.S. patents that have been identifiedherein, is incorporated herein in its entirety by this reference.

Other aspects, advantages, and modifications within the scope of theinvention will be apparent to those skilled in the art to which theinvention pertains. Various modifications, processes, as well asnumerous structures to which the embodiments of the invention may beapplicable will be readily apparent to those of skill in the art towhich the invention is directed upon review of the specification.Various aspects and features of the invention may have been explained ordescribed in relation to understandings, beliefs, theories, underlyingassumptions, and/or working or prophetic examples, although it will beunderstood that the invention is not bound to any particularunderstanding, belief, theory, underlying assumption, and/or working orprophetic example. Although various aspects and features of theinvention may have been described largely with respect to applications,or more specifically, medical applications, involving diabetic humans,it will be understood that such aspects and features also relate to anyof a variety of applications involving non-diabetic humans and any andall other animals. Further, although various aspects and features of theinvention may have been described largely with respect to applicationsinvolving partially implanted sensors, such as transcutaneous orsubcutaneous sensors, it will be understood that such aspects andfeatures also relate to any of a variety of sensors that are suitablefor use in connection with the body of an animal or a human, such asthose suitable for use as fully implanted in the body of an animal or ahuman. Finally, although the various aspects and features of theinvention have been described with respect to various embodiments andspecific examples herein, all of which may be made or carried outconventionally, it will be understood that the invention is entitled toprotection within the full scope of the appended claims.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the embodiments of the invention, and are not intended tolimit the scope of what the inventors regard as their invention nor arethey intended to represent that the experiments below are all or theonly experiments performed. Efforts have been made to ensure accuracywith respect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

Example 1 Sensors Having Sensing Layers Incorporating a Low SurfaceTension Polymer

FIG. 6A illustrates problems that may be associated with sensor membranefabrication. The figure shows the so-called “coffee ring” effect whichresults in poor uniformity and/or distribution of one or more componentsof the sensing layer of a sensor (e.g., an enzyme-containing sensinglayer of such devices). In order to address these issues a low surfacetension polymer was incorporated into the sensing layer of the sensor.

In a comparison between a sensing layer formulation deposited on a goldsubstrate in which the sensing layer formulation was not supplementedwith a low surface tension polymer and a sensing layer formulationdeposited on a gold substrate in which a sensing layer formulation thatwas treated with a low surface tension polymer, the low surface tensionpolymer-treated sensing layer is smoother, more homogenous and uniformin distribution (see FIG. 6B) as compared to the sensing layer lackingthe low surface tension polymer (see FIG. 6A). Supplementing the sensinglayer formulation with a low surface tension polymer results in animproved sensing layer coating that eliminates a lack of uniformeddistribution and the “coffee ring” effect as shown in FIG. 6B.

When FIG. 6A is juxtaposed against FIG. 6B, they provide a comparisonbetween a sensing layer formulation deposited on a gold substrate inwhich the sensing layer formulation was not supplemented with a lowsurface tension polymer (FIG. 6A), versus a sensing layer formulationdeposited on a gold substrate with a sensing layer that was supplementedwith the low surface tension polymer dimethyl, methyl (polyethyleneoxide acetate-capped) siloxane (“DC 57”), (FIG. 6B). In addition, asevidenced by FIGS. 7 and 8, treatment with different low surface tensionpolymers, such as DC 28 (FIG. 7) and Surfynol® 2502 (FIG. 8) alsoresulted in a sensing layer that is smooth, homogenous and uniform indistribution.

Table 1 summarizes data relating to contact angle and percent change incontact angle as compared to a control sensing layer formulation forsensing layers supplemented with the low surface tension polymer DC 57at either 1% or 2% of total volume. As summarized below, inclusion of alow surface tension polymer at 1% of total volume decreases the contactangle by 32.7% and inclusion of a low surface tension polymer at 2% oftotal volume decreases the contact angle by 31.1%.

TABLE 1 Sample Contact Angle % Change Control 61° — 1% DC 57 41° −32.72% DC 57 42° −31.1

Table 2 summarizes data for three groups of sensors, includingcoefficient of variation between different sensors (% CV), time forresponse to analyte levels (time (response/min), sensitivity (nA/mM),and decay. The first group of sensors is control sensors having sensinglayers that lack a low surface tension polymer. The second and thirdgroups had sensing layers that were supplemented with either 1% DC 57(group 2) or 3% DC 57 (group 3). Sensors from each group were thentested after manufacture (0 days) or after storing for 11 days at 4° C.or 11 days at 56° C. to determine stability of the sensors.

TABLE 2 Group 1 - Control Group 2 - 1% DC 57 Group 3 - 3% DC 57 11 Days11 Days 11 Days 11 Days 11 Days 11 Days 0 Days @4° C. @56° C. 0 Days @4°C. @56° C. 0 Days @4° C. @56° C. Number of 8 8 8 8 8 8 7 8 8 sensorsnA/mM 0.578 0.562 0.452 0.471 0.502 0.408 0.591 0.66 0.502 % CV 11.510.2 6.3 10.6 6.2 6.6 6.7 12.3 5.3 nA/mM * mm² 8.25 8.02 6.46 6.73 7.176.01 8.44 9.43 7.17 Time 2:48 3:19 4:01 5:10 4:47 5:44 4:42 4:52 5:16(response/min) Decay/%/hr −0.04 0.06 −0.03 0.12 0.05 0.03 0.19 0.53 0.38Decay - −0.1 −0.06 −0.07 −0.06 −0.12 −0.12 0.01 0.11 0.09 no Hump Slope−19.6% −18.7% −23.9% Changed

FIG. 10 shows the results of sensitivity comparison (nA/mm²) at varyingconcentrations of glucose (mM) between control sensors (diamonds),sensors with the sensing layers supplemented with 1% of the low surfacetension polymer DC 57 (squares) and sensors with the sensing layerssupplemented with 3% of the low surface tension polymer DC 57(triangles). As demonstrated in FIG. 10, the low surface tension polymersupplemented sensing layers sensors had a similar sensitivity to thoselacking the low surface tension polymer.

Example 2 Sensors Having Membrane Incorporating a Low Surface TensionPolymer

FIG. 9 illustrates problems that may be associated with sensor membranefabrication, such as a polymeric glucose-limiting membrane formulationthat includes a heterocyclic nitrogen containing polymer (see forexample U.S. Pat. No. 6,932,894). The figure shows the so-called “orangepeel” effect of the membrane coating, which results in poor uniformityof the membrane on the substrate, such as a carbon substrate. In orderto address this issue a low surface tension polymer was incorporatedinto the polymer membrane of the sensor.

In a comparison between a control sensor in which the membraneformulation was not supplemented with a low surface tension polymer anda sensor in which a membrane formulation that was treated with a lowsurface tension polymer, the low surface tension polymer-treated sensormembrane is smoother, and more homogenous (see FIG. 9B) as compared tothe sensor membrane lacking the low surface tension polymer (see FIG.9A). Supplementing the membrane formulation with a low surface tensionpolymer results in an improved membrane coating that eliminateswrinkling and levels the “orange peel” effect as shown in FIG. 9B. WhenFIG. 9A is juxtaposed against FIG. 9B, they provide a comparison betweena control sensor in which the membrane formulation was not supplementedwith a low surface tension polymer 10 days post cure at 56° C. (FIG.9A), versus a sensor with a membrane coating that was supplemented withthe low surface tension polymer DC 57 at 0.05% of total volume (FIG.9B). After 16 days at 56° C., the DC 57-treated sensor membrane appearssmooth and homogenous.

In conclusion, the experiments above show that the addition of one ormore low surface tension polymers to an analyte sensor formulation, suchas a sensing layer or a polymeric glucose-limiting membrane, promotesthe uniformity and/or distribution of one or more components of themembrane formulation and elimination of the “coffee ring” effect ofsettling of sensing layer components at the perimeter of the formulationon the sensor surface. Furthermore, the addition of one or more lowsurface tension polymers to an analyte sensor membrane formulation alsopromotes the uniformity of the membrane, eliminating the “orange peel”effect and wrinkles, thus improving the manufacturing yield.

That which is claimed is:
 1. An electrode comprising: a sensing layerdisposed thereon, and a membrane disposed over the sensing layercomprising a low surface tension polymer selected frompolydimethylsiloxane (H₃C)₃Si[Si(CH₃)₂O]_(n)Si(CH₃)₃, polyether modifiedpolydimethylsiloxane [CH₂O—]_(n)[Si(CH₃)₂O]_(n)—[CH₂O—]_(n),poly((eo)(po))butyl terminated polydimethylsiloxaneCH₃—{[CH₂CH₂O]_(n)—[CH₂O—]_(n)}_(n)[Si(CH₃)₂O]_(n)—{[CH₂O—]_(n)[CH₂CH₂O]_(n)}_(n)—CH₃,and dimethyl, methyl (polyethylene oxide acetate-capped) siloxane,wherein n is an integer in a range of from about 1 to 500, wherein thelow surface tension polymer comprises 1% or less by weight of the totalformulation of the membrane.
 2. The electrode of claim 1, wherein atleast a portion of the electrochemical analyte electrode is adapted tobe subcutaneously positioned in a subject.
 3. The electrode of claim 1,wherein the low surface tension polymer comprises a substituted orunsubstituted polyacrylate polymer or a substituted or unsubstitutedpolysiloxane polymer.
 4. The electrode of claim 1, wherein the lowsurface tension polymer comprises polyether-modifiedpolydimethylsiloxane.
 5. The electrode of claim 1, wherein the sensinglayer comprises a glucose-responsive enzyme.
 6. The electrode of claim5, wherein the glucose-responsive enzyme is glucose oxidase.
 7. Theelectrode of claim 1, wherein the sensing layer comprises a redoxmediator.
 8. The electrode of claim 7, wherein the redox mediatorcomprises a ruthenium-containing complex or an osmium-containingcomplex.
 9. The electrode of claim 1, wherein the sensing layercomprises a polymer.
 10. The electrode of claim 9, wherein the polymeris covalently bound to a glucose responsive enzyme or a redox mediator.11. The electrode of claim 9, wherein the polymer is a hydrophilicpolymer.
 12. The electrode of claim 1, wherein the electrode isconfigured for use in an in vivo sensor.
 13. The electrode of claim 1,wherein the electrode is configured for use in an in vitro sensor.